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The kinase suppressor of Ras KSR modulat ... tion from MAP kinase activation
The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation.
17
The Ras GTPase plays an essential role in many cellular signal transduction events. Activation of the mitogen activated protein (MAP) kinase is a primary consequence of Ras activation and plays a key role in mediating Ras signal transduction. A novel kinase, KSR, has recently been functionally isolated as a positive regulator of Ras signaling in Caenorhabditis elegans vulval induction and Drosophila photoreceptor differentiation. We have examined the effect of KSR on growth factor and Ras-induced MAP kinase signaling in mammalian cells. Surprisingly, we observed that KSR specifically blocks EGF and Ras-induced phosphorylation and activation of ternary complex factors (TCF), physiological substrates of MAP kinases, without affecting the activation of MAP kinase itself. A kinase-deficient mutant of KSR, KSR-RM, appears to function as a dominant interfering mutant which elevates phosphorylation of Elk-1, a member of the TCF family, and Elk-1-dependent transcription. The effect of KSR on Elk-1 was significantly decreased by inhibition of calcineurin, a putative Elk-1 phosphatase. These observations demonstrate that KSR is capable of uncoupling the MAP kinase activation from its target phosphorylation, and thus provide a novel mechanism for modulating the Ras-MAP kinase signaling pathway. This study provides the first evidence that signal output of MAP kinase cascades is subject to regulation at a level independent of MAP kinase activity.
Sugimoto T, Stewart S, Han M, Guan KL
The EMBO journal
1998-03-16 00:00
17
6
1717-27
3T3 Cells,Animals,COS Cells,Ca(2+)-Calmodulin Dependent Protein Kinase,Calcineurin,Cyclosporine,DNA-Binding Proteins,Enzyme Activation,Enzyme Inhibitors,Epidermal Growth Factor,Genes, fos,Genes, jun,MAP Kinase Kinase 1,Mice,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinase Kinases,Mitogen-Activated Protein Kinases,Mutation,Phosphorylation,Protein Kinases,Protein-Serine-Threonine Kinases,Protein-Tyrosine Kinases,Proto-Oncogene Proteins,Recombinant Fusion Proteins,Signal Transduction,Trans-Activation (Genetics),Transcription Factors,ets-Domain Protein Elk-1,ets-Domain Protein Elk-4,ras Proteins,DNA-Binding Proteins,Elk1 protein, mouse,Elk4 protein, mouse,Enzyme Inhibitors,Proto-Oncogene Proteins,Recombinant Fusion Proteins,Transcription Factors,ets-Domain Protein Elk-1,p62TCF protein, mouse,ets-Domain Protein Elk-4,Cyclosporine,Epidermal Growth Factor,KSR-1 protein kinase,MAP Kinase Kinase 1,MAP2K1 protein, human,Map2k1 protein, mouse,Mitogen-Activated Protein Kinase Kinases,Protein-Tyrosine Kinases,Ca(2+)-Calmodulin Dependent Protein Kinase,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinases,Protein Kinases,Protein-Serine-Threonine Kinases,Calcineurin,ras Proteins
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0606, USA
EMBO J.
NIGMS GM47869, NIGMS GM51586, NCI T32 CA09676
0261-4189
10.1093/emboj/17.6.1717
526
True
9501093
